Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models

Ghanashyam D. Ghadge; Barbara S. Slusher; Amos Bodner; Mauro Dal Canto; Krystyna Wozniak; Ajit G. Thomas; Camilo Rojas; Takashi Tsukamoto; Pavel Majer; Richard J. Miller; Anna Liza Monti; Raymond P. Roos

doi:10.1073/pnas.1530168100

Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models

Ghanashyam D. Ghadge, Barbara S. Slusher, Amos Bodner, Mauro Dal Canto, Krystyna Wozniak, Ajit G. Thomas, Camilo Rojas, Takashi Tsukamoto, Pavel Majer, Richard J. Miller, Anna Liza Monti, Raymond P. Roos^*

^*Corresponding author for this work

Pharmacology

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Abstract

Approximately 10% of cases of amyotrophic lateral sclerosis (ALS), a progressive and fatal degeneration that targets motor neurons (MNs), are inherited, and ≈20% of these cases of familial ALS (FALS) are caused by mutations of copper/zinc superoxide dismutase type 1. Glutamate excitotoxicity has been implicated as a mechanism of MN death in both ALS and FALS. In this study, we tested whether a neuroprotective strategy involving potent and selective inhibitors of glutamate carboxypeptidase II (GCPII), which converts the abundant neuropeptide N-acetylaspartylglutamate to glutamate, could protect MNs in an in vitro and animal model of FALS. Data suggest that the GCPII inhibitors prevented MN cell death in both of these systems because of the resultant decrease in glutamate levels. GCPII inhibition may represent a new therapeutic target for the treatment of ALS.

Original language	English (US)
Pages (from-to)	9554-9559
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	100
Issue number	16
DOIs	https://doi.org/10.1073/pnas.1530168100
State	Published - Aug 5 2003

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Ghadge, G. D., Slusher, B. S., Bodner, A., Dal Canto, M., Wozniak, K., Thomas, A. G., Rojas, C., Tsukamoto, T., Majer, P., Miller, R. J., Monti, A. L., & Roos, R. P. (2003). Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models. Proceedings of the National Academy of Sciences of the United States of America, 100(16), 9554-9559. https://doi.org/10.1073/pnas.1530168100

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title = "Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models",

abstract = "Approximately 10% of cases of amyotrophic lateral sclerosis (ALS), a progressive and fatal degeneration that targets motor neurons (MNs), are inherited, and ≈20% of these cases of familial ALS (FALS) are caused by mutations of copper/zinc superoxide dismutase type 1. Glutamate excitotoxicity has been implicated as a mechanism of MN death in both ALS and FALS. In this study, we tested whether a neuroprotective strategy involving potent and selective inhibitors of glutamate carboxypeptidase II (GCPII), which converts the abundant neuropeptide N-acetylaspartylglutamate to glutamate, could protect MNs in an in vitro and animal model of FALS. Data suggest that the GCPII inhibitors prevented MN cell death in both of these systems because of the resultant decrease in glutamate levels. GCPII inhibition may represent a new therapeutic target for the treatment of ALS.",

author = "Ghadge, {Ghanashyam D.} and Slusher, {Barbara S.} and Amos Bodner and {Dal Canto}, Mauro and Krystyna Wozniak and Thomas, {Ajit G.} and Camilo Rojas and Takashi Tsukamoto and Pavel Majer and Miller, {Richard J.} and Monti, {Anna Liza} and Roos, {Raymond P.}",

year = "2003",

month = aug,

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doi = "10.1073/pnas.1530168100",

language = "English (US)",

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Ghadge, GD, Slusher, BS, Bodner, A, Dal Canto, M, Wozniak, K, Thomas, AG, Rojas, C, Tsukamoto, T, Majer, P, Miller, RJ, Monti, AL & Roos, RP 2003, 'Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models', Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 16, pp. 9554-9559. https://doi.org/10.1073/pnas.1530168100

Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models. / Ghadge, Ghanashyam D.; Slusher, Barbara S.; Bodner, Amos et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 16, 05.08.2003, p. 9554-9559.

Research output: Contribution to journal › Article › peer-review

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AU - Ghadge, Ghanashyam D.

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AU - Bodner, Amos

AU - Dal Canto, Mauro

AU - Wozniak, Krystyna

AU - Thomas, Ajit G.

AU - Rojas, Camilo

AU - Tsukamoto, Takashi

AU - Majer, Pavel

AU - Miller, Richard J.

AU - Monti, Anna Liza

AU - Roos, Raymond P.

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AB - Approximately 10% of cases of amyotrophic lateral sclerosis (ALS), a progressive and fatal degeneration that targets motor neurons (MNs), are inherited, and ≈20% of these cases of familial ALS (FALS) are caused by mutations of copper/zinc superoxide dismutase type 1. Glutamate excitotoxicity has been implicated as a mechanism of MN death in both ALS and FALS. In this study, we tested whether a neuroprotective strategy involving potent and selective inhibitors of glutamate carboxypeptidase II (GCPII), which converts the abundant neuropeptide N-acetylaspartylglutamate to glutamate, could protect MNs in an in vitro and animal model of FALS. Data suggest that the GCPII inhibitors prevented MN cell death in both of these systems because of the resultant decrease in glutamate levels. GCPII inhibition may represent a new therapeutic target for the treatment of ALS.

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Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models

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